1. Field of the Invention
The invention relates generally to compounds useful for the inhibition of certain thioesterases, and more specifically, to new compounds that include the β-lactone moiety or a β-lactam moiety that are useful as thioesterase inhibitors.
2. Background Information
The thioesterase superfamily contains a wide variety of enzymes, which exhibit esterase activity (i.e., splitting of an ester into acid and alcohol in the presence of water) specifically at a thiol group. This family includes, among others, 4HBT which catalyses the final step in the biosynthesis of 4-hydroxybenzoate from 4-chlorobenzoate in the soil dwelling microbe Pseudomonas CBS-3. The thioesterase superfamily also includes various cytosolic long-chain acyl-CoA thioester hydrolases. Long-chain acyl-CoA hydrolases hydrolyze palmitoyl-CoA to CoA and palmitate, as well as catalyse the hydrolysis of other long chain fatty acyl-CoA thioesters.
Human fatty acid synthase is a large homodimeric multifunctional enzyme that synthesizes palmitic acid. The unique carboxyl terminal thioesterase domain of fatty acid synthase hydrolyzes the growing fatty acid chain and plays a critical role in regulating the chain length of fatty acid released. Also, the up-regulation of human fatty acid synthase in a variety of cancer makes the thioesterase a candidate target for therapeutic treatment.
Recent studies have focused on the role of the thioesterase superfamily in various diseases, disorders and pathologies. While some compounds useful as inhibitors of various members of the thioesterase superfamily have been identified and synthesized, no compounds have been reported that are capable of targeting and inhibiting thioesterases such as human fatty acid synthase thioesterase.